Christel Renoux

Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study

Objectives To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy. Design Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date. Results There were 15 710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose. Conclusions The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.

Hormone replacement therapy and the risk of venous thromboembolism: a population-based study.

Summary.  Background: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. Methods: Among the United Kingdom’s General Practice Research Database, we identified the cohort of all women aged 50–79 between 1 January 1987 and 1 March 2008. Using a nested case–control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. Results: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89–1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77–1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77–1.10), relative to non‐use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37–1.63) and oral estrogen–progestogen (RR 1.54; 95% CI, 1.44–1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. Conclusion: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.

Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes

AIMS An increased risk of stroke was observed in two atrial fibrillation (AF) trials of oral factor Xa inhibitors, when patients were transitioned to open label warfarin at the end of the study. The objective of this study is to determine whether initiation of warfarin is associated with an increased risk of stroke in patients with AF. METHODS AND RESULTS Using the UK Clinical Practice Research Datalink, a nested case-control analysis was conducted within a cohort of 70 766 patients with AF between 1993 and 2008. Stroke cases were randomly matched with up to 10 controls on age, sex, date of AF diagnosis, and time since AF diagnosis. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) of stroke associated with current warfarin use classified according to time since initiation of treatment (<30 days, 31-90 days, and >90 days), when compared with non-use. A total of 5519 patients experienced a stroke during follow-up. Warfarin was associated with a 71% increased risk of stroke in the first 30 days of use (RR: 1.71, 95% CI: 1.39-2.12), while decreased risks were observed with initiation >30 days before the event (31-90 days: RR: 0.50, 95% CI: 0.34-0.75 and >90 days: RR: 0.55, 95% CI: 0.50-0.61, respectively). CONCLUSION Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, supporting the biological plausibility of a transient hypercoagulable state at the start of the treatment, although additional studies are needed to confirm these findings.

Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?

OBJECTIVES To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. DESIGN Case report. SETTING University hospital. PATIENT A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. RESULTS Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. CONCLUSIONS Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.

Trends in the prescription of novel oral anticoagulants in UK primary care

AIMS Novel oral anticoagulants (NOACs) are alternatives to vitamin-K antagonists (VKAs) for the prevention of thromboembolism. It is unclear how NOACs have been adopted in the UK since first introduced in 2008. The present study was conducted to describe the trends in the prescription of NOACs in the UK, including dabigatran, rivaroxaban and apixaban. METHODS Using the UKs Clinical Practice Research Datalink, the rates of new use of NOACs and VKAs from 2009 to 2015 were calculated using Poisson regression. Patient characteristics associated with NOAC initiation were identified using multivariate logistic regression. RESULTS The overall rate of oral anticoagulant initiation increased by 58% over the study period [rate ratio (RR) 1.58; 95% confidence interval (CI) 1.23, 2.03], even as the rate of new VKA use decreased by 31% (RR 0.69; 95% CI 0.52, 0.93). By contrast, the rate of initiation of NOAC increased, particularly from 2012 onwards, with a 17-fold increase from 2012 to 2015 (RR 17.68; 95% CI 12.16, 25.71). In 2015, NOACs accounted for 56.5% of oral anticoagulant prescriptions, with rivaroxaban prescribed most frequently, followed by apixaban and then dabigatran. Compared to VKAs, new NOAC users were less likely to have congestive heart failure, coronary artery disease and peripheral vascular disease, and more likely to have a history of ischaemic stroke. CONCLUSIONS In the UK, the rate of initiation of NOACs has increased substantially since 2009, and these agents have now surpassed VKAs as the anticoagulant of choice. Moreover, the characteristics of patients initiated on NOACs have changed over time, and this should be accounted for in future studies comparing NOACs and VKAs.

Association of Selective Serotonin Reuptake Inhibitors With the Risk for Spontaneous Intracranial Hemorrhage

Importance Selective serotonin reuptake inhibitors (SSRIs) may increase the risk for spontaneous intracranial hemorrhage (ICH), an effect that is in theory linked to the strength of inhibition of serotonin reuptake of an antidepressant. However, whether antidepressants that are strong inhibitors of serotonin reuptake actually increase the risk for ICH and the effect of concomitant use of antithrombotics are unknown. Objectives To assess the risk for ICH associated with the use of SSRIs compared with tricyclic antidepressants (TCAs) among new users of antidepressants and according to the relative affinity of the antidepressant for the serotonin transporter and to assess whether concomitant use of antithrombotics modifies this risk. Design, Setting, and Participants This population-based cohort study included new users of antidepressants 18 years or older from January 1, 1995, to June 30, 2014. More than 650 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink enrolled patients. with use of a nested case-control approach, each case of a first ICH identified during follow-up was matched with as many as 30 control individuals by age, sex, calendar time, and duration of follow-up. Follow-up was completed on October 31, 2014. Interventions Current use of SSRIs compared with TCAs and strong compared with weak serotonin reuptake inhibitors. Main Outcomes and Measures Incidence rate ratios (RRs) of ICH. Results Among a cohort of 1 363 990 incident users of antidepressants (36.8% male; 63.2% female; mean [SD] age, 47.9 [18.5] years), 3036 cases of ICH were identified during follow-up and matched to 89 702 controls. Current SSRI use was associated with an increased risk for ICH (RR, 1.17; 95% CI, 1.02-1.35) relative to TCAs, highest during the first 30 days of use (RR, 1.44; 95% CI, 1.04-1.99), and translating in very few additional events. Similarly, the risk was increased by 25% with strong inhibitors (RR, 1.25; 95% CI, 1.01-1.54) and highest during the first 30 days of use (RR, 1.68; 95% CI, 0.90-3.12). Concomitant use of anticoagulants may increase the risk substantially (RR, 1.73; 95% CI, 0.89-3.39). Conclusions and Relevance The use of SSRIs and more generally of antidepressants with strong inhibition of serotonin reuptake are associated with an increased risk for ICH, particularly in the first 30 days of use and when used concomitantly with oral anticoagulants.

Hormone replacement therapy use and the risk of stroke

OBJECTIVES Randomised trials reported an increase risk of stroke with an estrogen plus progestogen formulation of hormone replacement therapy (HRT). A recent trial also reported an increased risk with tibolone, a selective tissue estrogenic activity regulator. METHODS We used the General Practice Research Database to conduct a case-control study within a cohort of women aged 50-79 between January 1987 and October 2006, without history of stroke prior to cohort entry. We identified all cases of stroke occurring during the study period and selected up to four controls matched to each case on age, general practice and year of start in the practice. Information on HRT use during the year preceding the index date was obtained. Conditional logistic regression was used to estimate the rate ratios of stroke associated with current use of the different HRTs. RESULTS The cohort included 870,286 women, of whom 15,710 experienced a stroke during follow-up and were matched to 59,958 controls. The adjusted rate ratio of stroke associated with current use of tibolone relative to non-use of HRT was 1.08 (95% CI: 0.82-1.44). The rate ratios with current use of estrogens alone and estrogen plus progestogen were 1.26 (95% CI: 1.10-1.45) and 1.19 (95% CI: 1.05-1.36) respectively. CONCLUSIONS We found no evidence of an elevated risk of stroke associated with the use of tibolone, although the low number of subjects using tibolone does not permit to rule out a small risk. The small elevated risk of stroke with estrogens or estrogens plus progestogen is consistent with that reported in randomised trials.

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study

Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism. Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016. Setting Community based, using healthcare data from six jurisdictions in Canada and the United States. Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis. Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites. Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients. Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment. Trial registration Clinical trials NCT02833987.

Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: a population-based cohort study

Objectives Hepatic enzyme-inducing antiepileptic drugs (AEDs) increase serum lipid levels and other atherogenic markers via the induction of cytochrome P450 and may therefore increase the risk of vascular events. We sought to assess the risk of ischaemic stroke and myocardial infarction (MI) according to AED enzymatic properties. Design Population-based cohort study with nested case–control analysis. Setting 650 general practices in the UK contributing to the Clinical Practice Research Datalink. Participants A cohort of 252 407 incident AED users aged 18 or older between January 1990 and April 2013. For each case of ischaemic stroke or MI, up to 10 controls were randomly selected among the cohort members in the risk sets defined by the case and matched on age, sex, indication for AED, calendar time and duration of follow-up. Interventions Current use of enzyme-inducing and enzyme-inhibiting AEDs compared with non-inducing AEDs. Primary outcome measures Incidence rate ratios (RRs) of ischaemic stroke and MI. Results 5069 strokes and 3636 MIs were identified during follow-up. Inducing AEDs use was associated with a small increased risk of ischaemic stroke (RR=1.16, 95% CI 1.02 to 1.33) relative to non-inducing AEDs, most likely due to residual confounding. However, current use of inducing AEDs for ≥24 months was associated with a 46% increased risk of MI (RR=1.46, 95% CI 1.15 to 1.85) compared with the same duration of non-inducing AED, corresponding to a risk difference of 1.39/1000 (95% CI 0.33 to 2.45) persons per year. Current use of inhibiting AED was associated with a decreased risk of MI (RR=0.81, 95% CI 0.66 to 1.00). Conclusions The use of enzyme-inducing AEDs was not associated with an increased risk of ischaemic stroke; a small increase of MI with prolonged use was observed. In contrast, use of inhibiting AEDs was associated with a decreased risk of MI.

Confounding by Pre-Morbid Functional Status in Studies of Apparent Sex Differences in Severity and Outcome of Stroke

Background and Purpose— Several studies have reported unexplained worse outcomes after stroke in women but none included the full spectrum of symptomatic ischemic cerebrovascular events while adjusting for prior handicap. Methods— Using a prospective population-based incident cohort of all transient ischemic attack/stroke (OXVASC [Oxford Vascular Study]) recruited between April 2002 and March 2014, we compared pre-morbid and post-event modified Rankin Scale score (mRS) in women and men and change in mRS score 1 month, 6 months, 1 year, and 5 years after stroke. Baseline stroke-related neurological impairment was measured with the National Institutes of Health Stroke Scale. Results— Among 2553 patients (50.6% women) with a first transient ischemic attack/ischemic stroke, women had a worse handicap 1 month after ischemic stroke (age-adjusted odds ratio for mRS score, 1.35; 95% confidence interval, 1.12–1.63). However, women also had a higher pre-morbid mRS score compared with men (age-adjusted odds ratio, 1.58; 95% confidence interval, 1.36–1.84). There was no difference in stroke severity when adjusting for age and pre-morbid mRS (odds ratio, 1.10; 95% confidence interval, 0.90–1.35) and no difference in the pre-/poststroke change in mRS at 1 month (age-adjusted odds ratio, 1.00; 95% confidence interval, 0.82–1.21), 6 months, 1 year, and 5 years. Women had a lower mortality rate, and there was no sex difference in risk of recurrent stroke. Conclusions— We found no evidence of a worse outcome of stroke in women when adjusting for age and pre-morbid mRS. Failure to account for sex differences in pre-morbid handicap could explain contradictory findings in previous studies. Properties of the mRS may also contribute to these inconsistencies.